Abstract Asthma is a chronic inflammatory airway disease, with an increasing prevalence, that is associated with a substantial burden on quality of life for patients and financial burden on society. Despite progress in the pharmacological treatment, overall asthma control remains unsatisfactory and treatment non-adherence is extremely high. The available research, much of which was conducted by investigators on this proposal, suggests that asthma may be associated with changes in brain structure and biochemistry, as well as increased risk for cognitive impairment and dementia. However, little is known about the impact of asthma on cognitive function and associated central nervous system processes, especially for in middle- to older age patients. Prior research has also not characterized the relationship between key domains of cognitive function and possible changes in brain structure, chemistry, and function specific to asthma. Additionally, the role of biobehavioral factors (such as mood, sleep, or inflammation) and asthma-specific factors (severity, duration, medication, airway inflammation) in explaining some of these deficits in asthma and aging has not been explored. We therefore propose to compare 126 adults 40-69 years old, diagnosed with asthma, and stratified for age (three decades) and asthma severity, with 66 age-matched non-asthmatic controls using cognitive tests that include processing speed, episodic memory, and executive function. Participants will also undergo neuroimaging. Structural magnetic resonance imaging (MRI) will focus on hippocampal volume. Diffusion tensor imaging (DTI) will be used to measure integrity of white matter integrity, which is associated with processing speed. Proton magnetic resonance spectroscopy (1HMRS) will measure metabolites linked to neuronal degeneration (N-acetyl aspartate, NAA) and glial inflammation (myo-inositol, mI). Three functional MRI scans will measure brain activity under different cognitive conditions: (a) a resting state scan to examine functional connectivity of brain networks; (b) a subsequent memory task to assess the role of hippocampal activation in the service of memory encoding, and (c) a modulation task that measures the ability of the cognitive control network to increase brain activity in fronto-parietal regions as task demands increase. We will also examine whether cognitive impairments are mediated by distinct brain changes extrapolated from prior research on aging and pilot research on respiratory disease. In addition, we will study a potential role of depressive mood, sleep quality and systemic inflammation, as well as asthma-relevant variables in mediating these associations. We hypothesize that asthma patients, compared to controls, will demonstrate accelerated brain aging as demonstrated by cognitive deficits and brain changes, which increase in magnitude with older age. Thus, this proposal will provide fundamental information to develop future preventative and intervention efforts to mitigate the potentially adverse effects of asthma on brain and cognition. A multidisciplinary research team with extensive experience in mental health in asthma patients, as well as neuroimaging across the lifespan will conduct the study.